The Popes are a family who haven't been able to use their real identity for years. In the late sixties, the parents set a weapons lab afire in an effort to hinder the government's Vietnam war campaign. Ever since then, the Popes have been on the run with the authorities never far behind. Their survival is threatened when their eldest son falls in love with a girl, and announces his wish to live his life on his own terms.

Running on Empty largely skims past its political themes, but River Phoenix's performance helps anchor the story's generational conflict.